Molecular analysis for microenvironment of hematopoietic cells.

造血细胞微环境的分子分析。

• 批准号: 10307024
• 负责人: SUDA Toshio
• 金额: $ 25.15万
• 依托单位: KUMAMOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10307024/
• 关键词: Microenvironment; Hemangioblast; Vitellin artery; Cell adhesion; Interaction between HSCs and ECs; Maintenance of stemness; Angiopoietin(Ang-1); TIE2 receptor; 造血-血管内皮相互作用; 末分化維持; 一次造血; AGM領域; 二次造血; 受容体型チロシンキナーゼTIE2; Angiopoietin; インテグリン

The association between hemopoietic stem cells (HSCs) and their microenvironment is central to the development and maintenance of a functional hematopoietic system.We clarified following 4 points.(1) We have investigated the function of TIE2 in the development of definitive hematopoiesis during embryogenesis. In vitellin artery, TIE2^+ hemopoietic cells aggregated and adhered to TIE2^+ endothelial cells (Immunity, 1998). Single TIE2^+ cells generated hematopoietic cells and endothelial cells(ECs) simultaneously. This TIE2^+ cells is identified as hemangioblasts(Blood, 1999).(2) A TIE2-ligand, angiopoietin-1 (Ang-1) promoted the adhesion of TIE2^+ HSCs to fibronectin through integrins. This adhesion enhances not only the proliferation of hematopoietic progenitor cells but also the maintenance of stemness (Immunity, 1998).(3) We found that Ang-1 derived from TIE2^+ HSCs promoted vessel sprouting into avascular areas (Cell, 2000). This suggests a close interaction between HSCs and ECs.(4) IL-3-dependent BaF cells transfected constitutive active form of TIE2 receptor kinase represented long survival without IL-3. This indicates two possibilities ; one is the changes of cell cycle by adhesion and the other is the avoidance of apoptosis through TIE2 signaling. It is likely that hemopoietic stem cells forms their own microenvironment (Niche) by the adhesion to stromal cells or cell matrix.

造血干细胞（HSC）与其微环境之间的关联对于功能性造血系统的发育和维持至关重要。我们阐明了以下四点。（1）我们研究了TIE2在胚胎发生过程中确定性造血发育中的功能。在卵黄动脉中，TIE2^+ 造血细胞聚集并粘附到 TIE2^+ 内皮细胞上（Immunity，1998）。单个TIE2^+细胞同时产生造血细胞和内皮细胞（EC）。该TIE2^+细胞被鉴定为成血管细胞（Blood，1999）。（2）TIE2配体血管生成素-1（Ang-1）通过整合素促进TIE2^+HSC与纤连蛋白的粘附。这种粘附不仅增强造血祖细胞的增殖，而且增强干细胞的维持（Immunity，1998）。（3）我们发现源自TIE2^+ HSC的Ang-1促进血管萌发到无血管区域（Cell，2000）。这表明HSCs和ECs之间存在密切的相互作用。(4)转染TIE2受体激酶的组成型活性形式的IL-3依赖性BaF细胞在没有IL-3的情况下表现出长期存活。这表明两种可能性；一是通过粘附改变细胞周期，二是通过TIE2信号传导避免细胞凋亡。造血干细胞很可能通过粘附基质细胞或细胞基质形成自己的微环境（Niche）。

项目成果

Huang X-L: "In vitro effecta of angiopoietins and VEGF on hematopoietic and endotherial cells."Biochem Biophys Res Comm. 264. 133-138 (1999)

黄晓丽：“血管生成素和VEGF对造血细胞和内皮细胞的体外作用。”Biochem Biophys Res Comm.

Kume A: "Green fluorecent protein as a selectable marker of retrovirally transduced hematopoietic progenitors."Stem Cells. 17. 226-232 (1999)

Kume A：“绿色荧光蛋白作为逆转录病毒转导的造血祖细胞的选择标记。”干细胞。

Mera A: "Induction of cell shape changes through activation of the interleukin-3 common b chain receptor by the RON receptor-type tyrosine kinase."JBC. 274. 15766-15774 (1999)

Mera A：“通过 RON 受体型酪氨酸激酶激活白细胞介素 3 共同 b 链受体来诱导细胞形状变化。”JBC。

Hirao A: "Overexpression of c-terminal src kinase homologous kinase supresses activation of lyntyrosine kinase required for VLA5-mediated Dami cell spreading." J Biol Chem. 273. 10004-10010 (1998)

Hirao A：“C 端 src 激酶同源激酶的过度表达会抑制 VLA5 介导的 Dami 细胞扩散所需的林酪氨酸激酶的激活。”

Duan Y: "Expression and functional analysis of hemopoietic progenitor antigen. NJ-1(114/A10), in the megakaryocytic lineage."Biochem Biophys Res Comm. 253. 401-406 (1998)

段Y：“造血祖抗原的表达和功能分析。NJ-1（114/A10），在巨核细胞谱系中。”Biochem Biophys Res Comm。